PROJECT SUMMARY Alzheimer's disease (AD) is the most common form of dementia, characterized by both senile plaques composed of Amyloid-? (A?) peptide and neurofibrillary tangles (NFTs) composed of tau protein. By 2050, 13 million Americans and 160 million people globally are projected to develop AD. With the increasing incidence of AD and neurodegenerative tauopathies, the need to develop reliable therapies to slow or prevent disease progression is critical. A drug that can halt the progression of AD would improve outcomes for millions of patients. Therefore, InnoSense LLC (ISL) and collaborator, the University of Texas Medical Branch (UTMB), propose to develop CyphonatolTM (indocyanine photonanoparticle for tau oligomers), an AD theranostic using selective tau oligomer antibodies conjugated on photonic nanoparticles (pNP) which are loaded with indocyanine green (ICG) and curcumin (Cur). These nanosized (<50 nm) pNP will be delivered intranasally and will penetrate the blood brain barrier (BBB) without any side effect. Recently, UTMB developed tau soluble oligomer (Tolig) antibodies (Abs) T22 (rabbit polyclonal), and TOMA (mouse monoclonal) targeting Tolig, both showing significant correlation with AD severity. We will conjugate Tolig Ab on the surface of pNP using standard carbodiimide chemistry. This pNP will contain ICG, a near infrared (NIR) imaging agent, and Cur, a well-known drug for pathogenic protein disaggregation. ICG and Cur are Food and Drug Administration (FDA) and Generally Recognized as Safe (GRAS)-approved agents, while the micelles will be formulated from biocompatible, carboxyl-functionalized polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) triblock copolymers. Recently, NIR imaging has raised the importance of long wavelength (650?1450 nm) in illuminating tissue (up to 10 centimeters). The ICG in Cyphonatol will illuminate the tau aggregate in the brain tissue for easy detection and monitoring. In Phase I ISL will validate a proof-of-concept of Cyphonatol pNP formulation for intranasal delivery. We will (1) formulate pNP to contain ICG and Cur, (2) conjugate Tolig-specific Abs on the surface of the pNP to form Cyphonatol, (3) determine the release kinetics and toxicity of Tolig in vitro, (4) establish the feasibility of packaging Cyphonatol in an intranasal delivery device and (5) establish Cyphonatol bioavailability and bioefficacy in a working model. In Phase II, we will (1) expand our study with overexpressing human tau mice (Htau and P301L mice) in a larger cohort and (2) establish reproducibility, stability, pharmacokinetics, and bioefficacy within safe dose. Teaming with the university and industrial partners, ISL will build an efficient Tolig targeting drug to successfully reduce tau aggregation. We anticipate Cyphonatol will be safe, non-toxic, effectively disperse throughout the nasal cavity and reach the olfactory bulb mucosa/nerves. It will penetrate the BBB to target tau aggregates. Cyphonatol will improve AD outcomes by providing a therapy that will slow disease progress and/or cure AD.